Phosphodiesterase Type 5 and Cancers: Progress and Challenges

www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 58), pp: 99179-99202 Review Phosphodiesterase type 5 and cancers: progress and challenges Ines Barone1, Cinzia Giordano2, Daniela Bonofiglio1, Sebastiano Andò1 and Stefania Catalano1 1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy 2Centro Sanitario, University of Calabria, Arcavacata di Rende, CS, Italy Correspondence to: Ines Barone, email: [email protected] Stefania Catalano, email: [email protected] Keywords: phosphodiesterase, cancer, targeted therapy, biomarkers, chemoprevention Received: June 20, 2017 Accepted: September 23, 2017 Published: October 12, 2017 Copyright: Barone et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Cancers are an extraordinarily heterogeneous collection of diseases with distinct genetic profiles and biological features that directly influence response patterns to various treatment strategies as well as clinical outcomes. Nevertheless, our growing understanding of cancer cell biology and tumor progression is gradually leading towards rational, tailored medical treatments designed to destroy cancer cells by exploiting the unique cellular pathways that distinguish them from normal healthy counterparts. Recently, inhibition of the activity of phosphodiesterase type 5 (PDE5) is emerging as a promising approach to restore normal intracellular cyclic guanosine monophosphate (cGMP) signalling, and thereby resulting into the activation of various downstream molecules to inhibit proliferation, motility and invasion of certain cancer cells. In this review, we present an overview of the experimental and clinical evidences highlighting the role of PDE5 in the pathogenesis and prevention of various malignancies. Current data are still not sufficient to draw conclusive statements for cancer patient management, but could provide further rational for testing PDE5- targeting drugs as anticancer agents in clinical settings. INTRODUCTION measures, such as smoking control, vaccination (for liver and cervical cancers), early detection, and promotion of The current global demographic, epidemiologic and healthy behaviors. Moreover, the burden of suffering nutritional transitions signal an enormous cancer burden and premature deaths can be decreased through the use on society in countries of all income levels. The incidence of an appropriate therapy and palliative care [2]. Surgery, of cancer cases is on continuing growth also because of chemotherapy and radiotherapy are currently the three an increasing prevalence of established risk factors, such major treatments to prolong the survival of the majority as tobacco use, excess body weight, physical inactivity, of cancer patients, but clinical improvements are often infection and changes in the reproductive patterns associated to undesirable side effects on normal cells connected with urbanization and economic development. or tissues. Thus, as the biology of cancer has become Based on data from GLOBOCAN 2012, an estimated progressively understood on a molecular level, therapeutic 14.1 million new cancer cases and 8.2 million deaths were research has mainly shifted its focus from cytotoxic recorded in 2012 globally [1]. Breast and lung cancers oncology drugs to newer target-based agents able to inhibit represent the most frequently diagnosed cancers and specifically tumor outgrowth and progression mechanisms the leading causes of cancer death in women and men, or enhance host immune responses against cancer cells. respectively, in the world and in less developed countries. On the other hand, clinical trials and meta-analyses have Other frequently diagnosed cancers worldwide include demonstrated that simultaneous or sequential multi- those of the prostate, liver, stomach, and colorectum modal therapies may improve patient outcome, may have among males and those of the stomach, cervix uteri, and acceptable tolerability profiles and may be active against a colorectum among females. A substantial proportion of variety of tumor types as compared with a single-modality cases can be prevented by broadly adoption of effective therapy [3–6]. In the search of molecularly targeted www.impactjournals.com/oncotarget 99179 Oncotarget cancer therapy, tremendous interest has been given to the intracellular sites, organelles and membranes as well as expression and regulation of the phosphodiesterase type 5 for their incorporation into particular multimolecular (PDE5) as an important signaling modulator involved in regulatory complexes or signalosomes. The regulatory diverse aspects of tumor cell function. In the last decade, regions contain domains that can be subjected to diverse a significant number of studies have reported an increased types of modification (e.g., phosphorylation by various expression of PDE5 in several human cancers compared protein kinases), or sites that may interact with allosteric to normal or surrounding non-neoplastic tissues [7–10]. ligands (e.g., cGMP binding sites), selective effectors Concomitantly, PDE5 inhibitors have been examined (e.g., Ca2+/calmodulin), protein partners (e.g., RAF1), in multiple malignancies and cancer cell lines for their or molecular scaffolds (e.g., caveolin). In addition, direct anticancer activities, for their efficacy as chemo- N-terminal regulatory regions include dimerization sensitizers and for cancer chemoprevention (reviewed in domains and autoinhibitory modules as several PDEs exist [11, 12]). In this review, we will highlight the emerging as asymmetric homo- or heterodimers (e.g., in PDEs 1, 4, knowledge and our recent findings showing the role of and 5). Informations from the crystal structures of isolated PDE5 as a tumor biomarker as well as a potential target for catalytic cores of PDEs have revealed that these domains therapeutic strategies aimed at controlling and eventually exhibit the same topography, composed of aminoacids curing malignant diseases. First, we will briefly discuss folded into 16 helices [73]. The active site forms a deep the structure and the biological function of PDE5. Next, hydrophobic pocket that includes a histidine-rich PDE we will summarize the significance of PDE5 expression signature sequence motif and consensus metal binding on different cancer types in clinical settings as well as domains, represented by two Zn2+ binding motifs (motifs A in experimental cellular and animal models. The benefit and B – HX3HXnE/D) and an additional binding site whose of targeting PDE5 in cancer prevention or treatment will metals could be Mg2+, Mn2+ or Co2+ [73, 74]. In addition to be also discussed because of the numerous advantages of the conserved portions important for cyclic nucleotide and PDE5 inhibitors. inhibitor bindings, the catalytic domain also encompasses variable determinants that are responsible of PDE family- The superfamily of PDEs related substrate affinities and selectiveness [75]. As expected from their complex genomic Mammalian cyclic nucleotide phosphodiesterases organization, multiple PDE isoforms are expressed in (PDEs) constitute a large and complex family of almost all cells (Table 1) [75, 76]. However, some cells are ubiquitously distributed hydrolases that have the unique relatively enriched in specific PDEs (e.g., photoreceptor function of catalysing the hydrolytic breakdown of cyclic PDE6 exclusively expressed in retina rods and cones and adenosine monophosphate (cAMP) and cyclic guanosine in the pineal gland) as well as some PDE alterations are monophosphate (cGMP) into the biologically inactive tightly connected to different pathological conditions (e.g., derivates 5′-AMP and 5′-GMP, respectively. The PDE PDE4B abnormalities have been linked to schizophrenia superfamily contains 11 distinct gene families (PDEs [77]) [75, 76, 78]. Recently, genetic alterations or 1 to 11), that encode at least 100 distinct PDE isoforms overexpression in PDE genes were described to be through alternative mRNA splicing, multiple promoters associated with tumor development. Polymorphisms in the and transcription start sites in human, rat, and mouse [13]. genes encoding PDE8A and PDE11A have been associated The 11 PDEs can be grouped into three broad categories with a predisposition to developing certain adrenocortical based on their sequence homology as well as substrate [79], testicular [69], and prostatic [70] cancers. More specificity and selectivity. PDE4, PDE7 and PDE8 are importantly, PDE5 overexpression has been reported in specific for cAMP hydrolysis; PDE5, PDE6 and PDE9 several types of cancers [7–10]. are specific for cGMP hydrolysis; PDE1, PDE2, PDE3, PDE10 and PDE11 exhibit dual specificity, acting on PDE5 structure, regulation, distribution, cAMP and cGMP with different affinities depending on signalling and function the isoform (Figure 1 and Table 1) [13–72]. The different PDEs are modular proteins sharing the following common The human PDE5A gene is located on chromosome structural organization from N-terminus to C-terminus 4q264,5 and contains about 23 exons spanning (Figure 1): 1) a highly divergent regulatory domain in approximately 100 kilobases, with the first three exons the N-terminal portion; 2) a conserved catalytic core of being alternative exons encoding the isoform-specific approximately 270 amino acids (~ 35–50%

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